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PLoS One. 2014 Jan 9;9(1):e83987. doi: 10.1371/journal.pone.0083987. eCollection 2014.

TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.

Author information

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, United Kingdom ; Department of Hepatology, Barts Health NHS Trust, London, United Kingdom.
Departments of Exploratory Science, Discovery Biology, and Validation Biology, Biogen Idec Inc., Cambridge, Massachusetts, United States of America.
Department of Physiology, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.



Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH.


To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies.


In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes.


TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.

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